Comprehensive analysis of receptor tyrosine kinase activation in human melanomas reveals autocrine signaling through IGF-1R.
Melanomas depend on autocrine signals for proliferation and survival; however, no systematic screen of known receptor tyrosine kinases (RTKs) has been performed to identify which autocrine signaling pathways are activated in melanoma. Here, we performed a comprehensive analysis of 42 RTKs in six individual human melanoma tumor specimens as well as 17 melanoma cell lines, some of which were derived from the tumor specimens. We identified five RTKs that were active in almost every one of the melanoma tissue specimens and cell lines, including two previously unreported receptors, insulin-like growth factor receptor 1 (IGF-1R) and macrophage-stimulating protein receptor (MSPR), in addition to three receptors (vascular endothelial growth factor receptor, fibroblast growth factor receptor, and hepatocyte growth factor receptor) known to be autocrine activated in melanoma. We show, by quantitative real time PCR, that all melanoma cell lines expressed genes for the RTK ligands such as HGF, IGF-1, and MSP. Addition of antibodies to either IGF-1 or HGF, but not to MSP, to the culture medium blocked melanoma cell proliferation, and even caused net loss of melanoma cells. Antibody addition deactivated IGF-1R and hepatocyte growth factor receptors, as well as mitogen-activated protein kinase signaling. Thus, IGF-1 is a new growth factor for autocrine driven proliferation of human melanoma in vitro. Our results suggest that IGF-1-IGF-1R autocrine pathway in melanoma is a possible target for therapy in human melanomas.


A case of isolated giant plexiform neurofibroma involving all branches of the common peroneal nerve.
Plexiform neurofibroma is generally considered as a component of neurofibromatosis 1, and a great majority of the cases with plexiform neurofibroma display other symptoms related to neurofibromatosis. Plexiform neurofibromas occur frequently in the head and neck region due to the rich innervation of the area, however appear rarely in the extremities. We report here an isolated giant plexiform neurofibroma involving the common peroneal nerve branches without symptoms related to neurofibromatosis in a 5-year-old case. Surgical excision was performed due to pain and numbness in the leg, and against the possibility of malignant transformation due to sudden growth observed in the tumor. One month following the excision of all the reachable tumoral tissues, tendon transfer surgery was performed for the ankle and toe extensions. Our case stands as the only reported case of isolated giant plexiform neurofibroma involving the common peroneal nerve in the pediatric age.


Management of breast cancer after Hodgkin's disease.
To evaluate the incidence, detection, pathology, management, and prognosis of breast cancer occurring after Hodgkin's disease. Seventy-one cases of breast cancer in 65 survivors of Hodgkin's disease were analyzed. The median age at diagnosis was 24.6 years for Hodgkin's disease and 42.6 years for breast cancer. The relative risk for invasive breast cancer after Hodgkin's disease was 4.7 (95% confidence interval, 3.4 to 6. 0) compared with an age-matched cohort. Cancers were detected by self-examination (63%), mammography (30%), and physician exam (7%). The histologic distribution paralleled that reported in the general population (85% ductal histology) as did other features (27% positive axillary lymph nodes, 63% positive estrogen receptors, and 25% family history). Although 87% of tumors were less than 4 cm, 95% were managed with mastectomy because of prior radiation. Two women underwent lumpectomy with breast irradiation. One of these patients developed tissue necrosis in the region of overlap with the prior mantle field. The incidence of bilateral breast cancer was 10%. Adjuvant systemic therapy was well tolerated; doxorubicin was used infrequently. Ten-year disease-specific survival was as follows: in-situ disease, 100%; stage I, 88%; stage II, 55%; stage III, 60%; and stage IV, zero. The risk of breast cancer is increased after Hodgkin's disease. Screening has been successful in detecting early-stage cancers. Pathologic features and prognosis are similar to that reported in the general population. Repeat irradiation of the breast can lead to tissue necrosis, and thus, mastectomy remains the standard of care in most cases.


[Towards a more equitable distribution of resources and assessment of quality of care: validation of a comorbidity based case-mix system].
Equitable distribution of healthcare resources and fair assessments of providers' performance necessitates adjusting for case-mix. The feasibility and validity of applying case-mix measures, based on inpatient and outpatient diagnoses, has yet to be tested in Israel. Assessment of the feasibility and validity of applying the Johns-Hopkins University Adjusted Clinical Groups (JHU-ACG) case-mix system, using diagnoses from hospitalizations or physician visits, at Clalit Health Services (CHS). A representative sample of 117,355 enrollees during 2006. The distribution of ACG morbidity groups and relative resource weights in CHS and the degree to which it corresponds to ACGs' distribution in other countries was examined. The degree to which ACGs can explain utilization of primary and specialty care in CHS was determined. ACGs explained a large percent of the variance in primary care and specialist visits (R2 = 38-54%), better than age and gender alone (R2 =12-13%). A high degree of correlation was found between the distribution of the population into ACG groups in CHS and samples from Canada or the United States (r = 0.91), and between the relative resource use for each ACG at CHS compared to the Canadian and US samples (r = 0.78-0.98). The JHU-ACG case-mix system can be applied in the Largest healthcare organization in Israel based on diagnoses generated at hospitalizations and physician visits. The system can now be applied for a variety of purposes, including resource allocation according to medical need, and for conducting fair assessments of providers' performance, which are currently being tested by CHS.


Hydration Status and Perception of Fluid Loss in Male and Female University Rugby Union Players.
Rugby union players are at risk for dehydration due to the high physiologic demand of the sport (~7.5 MJ/game). Dehydration could be due to lack of knowledge of fluid lost during activity. Therefore, the purpose of this study was to observe the hydration status and sweat loss estimations of male and female university rugby union players over three consecutive training sessions. Body mass, urine specific gravity (USG), and self-reported thirst scores were recorded pre and post training sessions. Sweat loss estimations were recorded post training session. After estimations, participants were shown his or her actual sweat loss in hopes of improving estimations over the three sessions. Paired t-tests were used to determine significance between pre and post training USG, thirst level and body mass for each day. A general linear mixed-effect model was used to determine significance of the difference between variables within gender and within days. Mean body mass changes did not exceed 2% lost for either gender on any of the three training sessions. Males significantly underestimated sweat loss by ~81% (p<0.01) after session one and improved estimations to ~36% after session three, however still significantly underestimated (p<0.01). Females also significantly underestimated sweat loss by ~64% on day one (p<0.01), and also improved estimations to ~60% on day three, however, still significantly underestimated (p<0.01). Results indicate that, on average, the participants remained in a euhydrated state throughout the training sessions. Findings also show that through education participants can improve perceptions of sweat loss to remain in euhydrated state.


Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.


Temporary Blindness after Inferior Alveolar Nerve Block.
Inferior Alveolar Nerve Block (IANB) anaesthesia is one of the common procedures in dental clinic. This procedure is safe, but complications may still occur. Ocular complications such as diplopia, loss of vision, or ophthalmoplegia are extremely rare. This case report explains an event where due to individual anatomic variation of the sympathetic vasoconstrictor nerve and maxillary and middle meningeal arteries, intravascular administration of anaesthetic agent caused unusual ocular signs and symptoms such as temporary blindness.


Quality indicators for palliative and end of life care: a review of Swedish policy documents.
All patients with palliative and end of life care needs should be guaranteed equal and safe treatment and care, regardless of their disease or site of care. The inclusion of quality indicators in national guidelines and other guiding documents supports quality assurance and improvement in provision of care. The aim of this paper was to review existing quality indicators in national Swedish policy documents relevant to palliative and end of life care. We reviewed existing guidelines for diseases expected to require palliative care issued by the National Board of Health and Welfare, existing regional clinical practice guidelines and the annual report of the Swedish Register of Palliative Care (SRPC) up until 2010. We found 11 quality indicators pertinent to palliative and end of life care in the guidelines for cancer diseases and 'The care and nursing of the elderly'. The indicators included assessment and treatment of pain, communication with the patient and the family, documentation in the patient record and registration in the SRPC. In the national guidelines for cardiology, pulmonary diseases, stroke, diabetes and dementia, there were no indicators relevant for palliative or end of life care. In the existing Swedish national guidelines for many different diseases, there is still a great need to define clinically relevant and feasible outcome measures of quality of palliative and end of life care.


Surveillance for antimicrobial resistance in Australian isolates of Clostridium difficile, 2013-14.
The objective of this study was to determine the activity of fidaxomicin and comparator antimicrobials against Clostridium difficile isolated from patients with C. difficile infection (CDI) in Australian hospitals and in the community. One private and one public laboratory from five states in Australia submitted a total of 474 isolates/PCR-positive stool samples during three collection periods in August-September 2013 (n = 175), February-March 2014 (n = 134) and August-September 2014 (n = 165). Isolate identification was confirmed by selective culture for C. difficile and a proportion of isolates from each state were characterized by PCR for toxin genes and PCR ribotyping. MICs of fidaxomicin and eight comparator antimicrobials were determined for all isolates using agar methodology. Site collection yielded 440 isolates of C. difficile and PCR revealed a heterogeneous strain population comprising 37 different PCR ribotypes (RTs), 95% of which were positive for tcdA and tcdB (A+B+). The most common RTs were 014 (29.8%) and 002 (15.9%). Epidemic RT 027 was not identified; however, small numbers of virulent RTs 078 and 244 were found. Resistance to vancomycin, metronidazole and fidaxomicin was not detected and resistance to moxifloxacin was very low (3.4%). Fidaxomicin showed potent in vitro activity against all 440 isolates (MIC50/MIC90 0.03/0.12 mg/L) and was superior to metronidazole (MIC50/MIC90 0.25/0.5 mg/L) and vancomycin (MIC50/MIC90 1/2 mg/L). These data confirm the potent in vitro activity of fidaxomicin against C. difficile. Moreover, this study provides an important baseline for ongoing long-term surveillance of antimicrobial resistance and prospective tracking of prominent and emerging strain types.


Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy.
Deletions of the long arm of chromosome 13 (13q-) are observed in patients with multiple myeloma (MM), are rarely observed in the monoclonal gammopathy of undetermined significance (MGUS) and have been associated with a worsened prognosis in MM. However, no minimally deleted region in the 13q arm has been defined at 13q, and consequently no tumor suppressor genes have yet been identified that are important for disease pathogenesis. We attempted to characterize these chromosome 13q deletions at the molecular cytogenetic level. We studied 351 newly diagnosed patients, entered into the E9486/E9487 clinical study of the Eastern Cooperative Oncology Group. Fluorescent in situ hybridization (FISH) combined with immune fluorescent detection (cIg-FISH) of clonal plasma cells (PC) and cytomorphology were used to analyze interphase, bone marrow (BM) cell, cytospin slides. We simultaneously used DNA probes for the following locus specific probes (LSI); LSI 13 (Rb) and D13S319, which hybridize to 13q14. We subsequently studied distal deletions using the D13S25 probe (13q14.3) and a subtelomeric probe (13qSTP) for the 13q-arm (D13S327) in 40 cases with documented LSI 13 (Rb)/D13S319 deletion and 40 without deletion of these loci. Of 325 evaluable patients, we found 13q deletions in 176 (54%) using LSI 13 (Rb) and D13S319 probes. Of 40 patients with LSI 13 (Rb)/D13S319 deletions, 34 (85%) had coexistent deletion of both D13S25/13qSTP. These results indicate that chromosome 13 deletions in MM involve loss of most if not all of the 13q arm perhaps even indicating monosomy. In six cases the 13qSTP signal was conserved, but D13S25 was lost indicating large interstitial deletions involving 13q14. In 39 of the 40 cases without LSI 13 (Rb)/D13S319 deletions, the normal pattern of two pairs of signals was observed for D13S25/13qSTP. Deletions involving 13q14 are very common in MM as detected by cIg-FISH. These deletions appear to predominantly involve loss of large segments of the 13q arm or monosomy 13, and only occasionally represent an interstitial deletion.


Economic evaluation of a web-based tailored lifestyle intervention for adults: findings regarding cost-effectiveness and cost-utility from a randomized controlled trial.
Different studies have reported the effectiveness of Web-based computer-tailored lifestyle interventions, but economic evaluations of these interventions are scarce. The objective was to assess the cost-effectiveness and cost-utility of a sequential and a simultaneous Web-based computer-tailored lifestyle intervention for adults compared to a control group. The economic evaluation, conducted from a societal perspective, was part of a 2-year randomized controlled trial including 3 study groups. All groups received personalized health risk appraisals based on the guidelines for physical activity, fruit intake, vegetable intake, alcohol consumption, and smoking. Additionally, respondents in the sequential condition received personal advice about one lifestyle behavior in the first year and a second behavior in the second year; respondents in the simultaneous condition received personal advice about all unhealthy behaviors in both years. During a period of 24 months, health care use, medication use, absenteeism from work, and quality of life (EQ-5D-3L) were assessed every 3 months using Web-based questionnaires. Demographics were assessed at baseline, and lifestyle behaviors were assessed at both baseline and after 24 months. Cost-effectiveness and cost-utility analyses were performed based on the outcome measures lifestyle factor (the number of guidelines respondents adhered to) and quality of life, respectively. We accounted for uncertainty by using bootstrapping techniques and sensitivity analyses. A total of 1733 respondents were included in the analyses. From a willingness to pay of €4594 per additional guideline met, the sequential intervention (n=552) was likely to be the most cost-effective, whereas from a willingness to pay of €10,850, the simultaneous intervention (n=517) was likely to be most cost-effective. The control condition (n=664) appeared to be preferred with regard to quality of life. Both the sequential and the simultaneous lifestyle interventions were likely to be cost-effective when it concerned the lifestyle factor, whereas the control condition was when it concerned quality of life. However, there is no accepted cutoff point for the willingness to pay per gain in lifestyle behaviors, making it impossible to draw firm conclusions. Further economic evaluations of lifestyle interventions are needed. Dutch Trial Register NTR2168; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2168 (Archived by WebCite at http://www.webcitation.org/6MbUqttYB).


TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers.
Neurons use neurotransmitters to communicate across synapses, constructing neural circuits in the brain. AMPA-type glutamate receptors are the predominant excitatory neurotransmitter receptors mediating fast synaptic transmission. AMPA receptors localize at synapses by forming protein complexes with transmembrane AMPA receptor regulatory proteins (TARPs) and PSD-95-like membrane-associated guanylate kinases. Among the three classes of ionotropic glutamate receptors (AMPA, NMDA, and kainate type), AMPA receptor activity is most regulatable by neuronal activity to adjust synaptic strength. Here, we mutated the prototypical TARP, stargazin, and found that TARP phosphorylation regulates synaptic AMPA receptor activity in vivo. We also found that stargazin interacts with negatively charged lipid bilayers in a phosphorylation-dependent manner and that the lipid interaction inhibited stargazin binding to PSD-95. Cationic lipids dissociated stargazin from lipid bilayers and enhanced synaptic AMPA receptor activity in a stargazin phosphorylation-dependent manner. Thus, TARP phosphorylation plays a critical role in regulating AMPA receptor-mediated synaptic transmission via a lipid bilayer interaction.


How epidemiology has challenged 3 prevailing concepts about atopic dermatitis.
We challenge 3 prevailing concepts in understanding atopic dermatitis using data from epidemiologic studies. First, we show that although atopy is associated with atopic dermatitis to some degree, its importance is not likely to be a simple cause-and-effect relationship, especially at a population level. Our epidemiologic data do not exclude a contributory role for IgE-mediated immunologic processes, especially in those with existing and severe disease. Second, evidence is presented that does not support a straightforward inverse relationship between infections and atopic dermatitis risk. A link, if present, is likely to be more complex, depending critically on the timing and type of infectious exposure. Third, recent evidence suggests that the risk of subsequent childhood asthma is not increased in children with early atopic dermatitis who are not also early wheezers, suggesting a co-manifestation of phenotypes rather than a progressive atopic march. Collectively, these observations underline the importance of epidemiologic studies conducted at a population level to gain a more balanced understanding of the enigma of atopic dermatitis.


Development and implementation of an electrolyte replacement protocol in the outpatient oncology infusion centers of a large academic healthcare system.
Patients receiving chemotherapy frequently experience electrolyte imbalances. Electrolyte replacement is, therefore, a necessity as patients may experience life-threatening symptoms.Study objective: The objective of this study was to evaluate the occurrence of low serum potassium and magnesium, and identify the rate of replacement for patients with low serum potassium and magnesium levels. Based on our findings, we developed and implemented a nursing-driven electrolyte replacement protocol. Preimplementation phase - A retrospective review for serum potassium and magnesium values obtained during infusion clinic visit between 1 August and 31 October 2016 was conducted. Implementation phase - A nursing-driven electrolyte replacement protocol with medication order "smart-set" and order selection intelligence within EPIC Beacon was developed and implemented in May 2017. Postimplementation phase - The postimplementation phase data were collected from 1 August to 30 November 2017 using a similar approach as the preimplementation phase. Preimplementation phase - During the preimplementation phase of the study, a total of 1495 serum potassium levels and 1193 serum magnesium levels were obtained. Among the 152 patients who needed potassium replacement, 34% (n = 52) were replaced and among the 118 serum magnesium levels that needed replacement, 30% (n = 35) were replaced. Postimplementation phase - 3979 serum potassium and 2707 magnesium levels were obtained. Among the 170 patients who needed potassium replacement, 75% (n = 127) were replaced. Among the 142 patients who needed magnesium replacement, 73% (n = 104) were replaced. A 121% increase in potassium replacement and a 143% increase in magnesium replacement were identified after implementing this protocol.


Salivary cytokines as a minimally-invasive measure of immune functioning in young children: correlates of individual differences and sensitivity to laboratory stress.
There is growing interest in minimally-invasive measures of environmentally-responsive biological systems in developmental science. Contributing to that endeavor, this study explores the intercorrelations, correlates, and task-sensitivity of proinflammatory salivary cytokines in childhood. Saliva was sampled from 125 healthy five-year old children (49% male) across a series of cognitive and emotional challenge laboratory tasks. Samples were assayed for cytokines (IL-1β, IL-6, IL-8, TNFα), and markers of hypothalamic-pituitary-adrenal (HPA) and autonomic nervous system (ANS) activation (salivary cortisol and alpha-amylase [sAA]). Cytokines were positively intercorrelated and task-sensitivity varied. Except IL-8, cytokines were elevated in children with oral health issues and tobacco smoke exposure. Among boys, cytokines were positively related to sAA and negatively related to cortisol. The findings suggest that in healthy children, salivary cytokine levels reflect compartmentalized oral immune activity. Associations between ANS and HPA activity and cytokines in saliva may present opportunities for minimally-invasive methods to explore neuroendocrine-immune interactions during development.


Molecular mechanisms of myocardial nitroso-redox imbalance during on-pump cardiac surgery.
The mechanism responsible for left ventricular dysfunction after cardiac surgery is only partly understood. In isolated rat hearts subjected to an ischaemia-reperfusion protocol, left ventricular dysfunction was associated with uncoupling of endothelial nitric oxide synthase (NOS) activity secondary to oxidation of the NOS cofactor, tetrahydrobiopterin (BH4). Here we investigated the effect of cardiopulmonary bypass and reperfusion on myocardial nitroso-redox balance in patients undergoing cardiac surgery. From 116 patients who underwent elective cardiac surgery on cardiopulmonary bypass, paired samples of the right atrial appendages were obtained before venous cannulation of the right atrium and after myocardial reperfusion. Superoxide production from atrial samples was measured by lucigenin (5 μmol/L) enhanced chemiluminescence and 2-hydroxyethidium (2-OHE) detection by high-performance liquid chromatography (HPLC). BH4, oxidised biopterins, GTP-cyclohydrolase 1 (GTPCH-1, the rate-limiting enzyme in BH4 synthesis), and NOS activity ((14)C L-arginine to L-citrulline conversion) were measured by HPLC. Atrial superoxide production increased significantly after reperfusion (from mean 37·83 relative light units per s per mg [SE 3·71] before cannulation to 65·02 [6·01] after reperfusion, p<0·0001; n=46 samples from 23 patients) due to increased mitochondrial and NOX2 oxidase activity (by 309% and 149%; p=0·002 and p=0·0002, respectively) and uncoupling of NOS activity. Atrial content of BH4 after perfusion was reduced (by 32%, p=0·001), as was activity of GTPCH1 (50%, p<0·0001). NOS activity decreased significantly after reperfusion (60%, p=0·0005) and this reduction was not affected by BH4 supplementation (10 μM) or NOX2 inhibition ex vivo. Instead, we identified increased endothelial NOS s-glutathionylation as the main mechanism for NOS uncoupling after reperfusion. Reversing NOS s-glutathionylation with dithiothreitol (100 μmol/L) completely restored NOS activity after reperfusion (p=0·34). Our findings suggest that NOS s-glutathionylation, rather than BH4 depletion, accounts for NOS dysfunction in patients after cardiac surgery and cardiopulmonary bypass. British Heart Foundation.


Research to improve extension ladder angular positioning.
A leading cause for extension ladder fall incidents is a slide-out event usually related to suboptimal ladder inclination. An improved ladder positioning method or procedure could reduce the risk of ladder stability failure and the related fall injury. The objective of the study was to comparatively evaluate the effectiveness of a multimodal angle indicator with other existing methods for extension ladder angular positioning. Twenty experienced and 20 inexperienced ladder users participated in the study. Four ladder positioning methods were tested in a controlled laboratory environment with 4.88 m (16 ft) and 7.32 m (24 ft) ladders in extended and retracted positions. The positioning methods included a no-instruction method, the current standard anthropometric method, and two instrumental methods - a bubble level indicator, and a multimodal indicator providing direct feedback with visual and sound signals. Performance measures included positioning angle and time. The results indicated that the anthropometric method was effective in improving the extension ladder positioning angle (p < 0.001); however, it was associated with considerable variability and required 50% more time than no-instruction. The bubble level indicator was an accurate positioning method (with very low variability), but required more than double the time of the no-instruction method (p < 0.001). The multimodal indicator improved the ladder angle setting as compared to the no-instruction and anthropometry methods (p < 0.001) and required the least time for ladder positioning among the tested methods (p < 0.001). An indicator with direct multimodal feedback is a viable approach for quick and accurate ladder positioning. The main advantage of the new multimodal method is that it provides continuous feedback on the angle of the device and hence does not require repositioning of the ladder. Furthermore, this indicator can be a valuable tool for training ladder users to correctly apply the current ANSI A14 standard anthropometric method in ladder angular positioning. The multimodal indicator concept has been further developed to become a hand-held tool in the form of a smart phone application.


Raw data normalization for a multi source inverse geometry CT system.
A multi-source inverse-geometry CT (MS-IGCT) system consists of a small 2D detector array and multiple x-ray sources. During data acquisition, each source is activated sequentially, and may have random source intensity fluctuations relative to their respective nominal intensity. While a conventional 3rd generation CT system uses a reference channel to monitor the source intensity fluctuation, the MS-IGCT system source illuminates a small portion of the entire field-of-view (FOV). Therefore, it is difficult for all sources to illuminate the reference channel and the projection data computed by standard normalization using flat field data of each source contains error and can cause significant artifacts. In this work, we present a raw data normalization algorithm to reduce the image artifacts caused by source intensity fluctuation. The proposed method was tested using computer simulations with a uniform water phantom and a Shepp-Logan phantom, and experimental data of an ice-filled PMMA phantom and a rabbit. The effect on image resolution and robustness of the noise were tested using MTF and standard deviation of the reconstructed noise image. With the intensity fluctuation and no correction, reconstructed images from simulation and experimental data show high frequency artifacts and ring artifacts which are removed effectively using the proposed method. It is also observed that the proposed method does not degrade the image resolution and is very robust to the presence of noise.


Empagliflozin Protects Cardiac Mitochondrial Fatty Acid Metabolism in a Mouse Model of Diet-Induced Lipid Overload.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent heart failure and decrease cardiovascular mortality in patients with type 2 diabetes. Heart failure is associated with detrimental changes in energy metabolism, and the preservation of cardiac mitochondrial function is crucial for the failing heart. However, to date, there are no data to support the hypothesis that treatment with a SGLT2 inhibitor might alter mitochondrial bioenergetics in diabetic failing hearts. Thus, the aim of this study was to investigate the protective effects of empagliflozin on mitochondrial fatty acid metabolism. Mitochondrial dysfunction was induced by 18 weeks of high-fat diet (HFD)-induced lipid overload. Empagliflozin was administered at a dose of 10 mg/kg in a chow for 18 weeks. Palmitate metabolism in vivo, cardiac mitochondrial functionality and biochemical parameters were measured. In HFD-fed mice, palmitate uptake was 1.7, 2.3, and 1.9 times lower in the heart, liver, and kidneys, respectively, compared with that of the normal chow control group. Treatment with empagliflozin increased palmitate uptake and decreased the accumulation of metabolites of incomplete fatty acid oxidation in cardiac tissues, but not other tissues, compared with those of the HFD control group. Moreover, empagliflozin treatment resulted in fully restored fatty acid oxidation pathway-dependent respiration in permeabilized cardiac fibers. Treatment with empagliflozin did not affect the biochemical parameters related to hyperglycemia or hyperlipidemia. Empagliflozin treatment preserves mitochondrial fatty acid oxidation in the heart under conditions of chronic lipid overload.


Lack of association between IL-6 gene polymorphisms and rheumatoid arthritis in Turkish population.
Inflammatory cytokines play an important role in the pathogenesis of rheumatoid arthritis (RA). One of candidate genes is interleukin-6 (IL-6), and single-nucleotide polymorphisms in the promoter region of IL-6 were found to be associated with RA. The aim of this study was to determine the association between IL-6 promoter polymorphisms (-174, -572, -597) and RA in Turkish population. A total of 425 subjects were recruited into the study (247 healthy controls and 178 RA). The promoter region of IL-6 gene was amplified by PCR using DNAs from patients and the controls, and their PCR products were digested by suitable enzymes. No significant association was found between RA and -174 genotype distribution (P = 0.535) and allele frequency (P = 0.230). There was also no relationship between -572 (P = 0.150) and -597 (P = 0.912) gene polymorphism and RA. Our results suggested that IL-6 gene promoter polymorphisms have no association with RA in Turkish population.


Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer.
Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma.


Diagnoses of Hidradenitis Suppurativa in the United States, 1979-2012.
Hidradenitis suppurativa (HS) is rarely diagnosed in the United States. Delayed diagnosis is a significant problem in the management of HS. In the past decade, there has been an increase in HS research. To determine whether those efforts have led to an increase in diagnoses, an analysis of visits to physicians in the United States from 1979 to 2012 was performed, using National Center for Health Statistics (NCHS) databases. Patient visits to private physician offices, hospital outpatient departments, and emergency rooms were analyzed. An increase in visit rates at outpatient departments from 2003-2007 [6.3/100,000, 95% confidence interval (CI) 2.9-9.8] to 2008-2010 (30.4/100,000, 95% CI 13.9-46.9; p = 0.017) was found. Converting the data to estimated numbers of patients, a 7-fold increase in patients from 2002-2007 (2.5/100,000, 95% CI 1.4-3.6) to 2008-2010 (16.9/100,000, 95% CI 7.8-26.1; p = 0.003) was found. No significant increase in patient or patient visit rates were found when analyzing visits in the physician office setting or combined office and hospital settings. Localization of increased diagnosis to outpatient departments may reflect the recent increase in clinical research. NCHS data can be useful in monitoring rates of HS diagnosis as an outcome of increased awareness of the disease.


Initial investigation of ¹⁸F-NaF PET/CT for identification of vertebral sites amenable to surgical revision after spinal fusion surgery.
A pilot study was performed in patients with recurrent back pain after spinal fusion surgery to evaluate the ability of (18)F-NaF PET/CT imaging to correctly identify those requiring surgical intervention and to locate a site amenable to surgical intervention. In this prospective study 22 patients with recurrent back pain after spinal surgery and with equivocal findings on physical examination and CT were enrolled for evaluation with (18)F-NaF PET/CT. All PET/CT images were prospectively reviewed with the primary objective of identifying or ruling out the presence of lesions amenable to surgical intervention. The PET/CT results were then validated during surgical exploration or clinical follow-up of at least 15 months. Abnormal (18)F-NaF foci were found in 16 of the 22 patients, and surgical intervention was recommended. These foci were located at various sites: screws, cages, rods, fixation hardware, and bone grafts. In 6 of the 22 patients no foci requiring surgical intervention were found. Validation of the results by surgery (15 patients) or on clinical follow-up (7 patients) showed that (18)F-NaF PET/CT correctly predicted the presence of an abnormality requiring surgical intervention in 15 of 16 patients and was falsely positive in 1 of 16. In this initial investigation, (18)F-NaF PET/CT imaging showed potential utility for evaluation of recurrent symptoms after spinal fusion surgery by identifying those patients requiring surgical management.


Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol.
Kawasaki disease (KD) is an acute self-limiting inflammatory vasculitis affecting predominantly medium-sized arteries, particularly the coronary arteries. A number of recent studies conducted in different European countries have demonstrated alarmingly high coronary complications despite treatment with intravenous immunoglobulin (IVIG). These high complication rates now emphasize the need for an urgent reappraisal of IVIG as the sole primary therapeutic agent for KD. The Kawasaki disease CAA prevention (KD-CAAP) trial will test the hypothesis that immediate adjunctive corticosteroid treatment to standard of care IVIG and aspirin will reduce coronary artery aneurysm (CAA) rates in unselected KD patients across Europe. KD-CAAP is a multicentre, randomised, controlled, open-label, blinded endpoint assessed trial that will be conducted across Europe supported by the conect4children pan-European clinical trials network. Patients with KD who satisfy the eligibility criteria will be randomised (1:1) to receive either oral prednisolone 2 mg/kg/day plus standard of care therapy IVIG (2 g/kg) and aspirin (40 mg/kg/day); or IVIG and aspirin alone. Further management is dictated by temperature and C-reactive protein (CRP) responses. Co-primary outcomes are as follows: (i) any CAA within the 3 months of trial follow-up; (ii) average estimate of maximum coronary Z-score at weeks 1, 2 and 6 adjusting for rescue treatment. Additional outcomes will be assessed including cost effectiveness, quality of life, corticosteroid toxicity and other safety outcomes. Several recent studies have indicated that coronary complications associated with KD across Europe are much higher than early trials of IVIG had initially suggested. KD-CAAP directly addresses this issue by exploring the therapeutic benefit of adjunctive corticosteroids in unselected KD cases. If we find that corticosteroids prevent CAA and are safe, this is a cheap and widely available intervention that could be implemented immediately for the benefit of children. ISRCTN71987471- March 31, 2020; Eudract 2019-004433-17.


Peptide Binding to a PDZ Domain by Electrostatic Steering via Nonnative Salt Bridges.
We have captured the binding of a peptide to a PDZ domain by unbiased molecular dynamics simulations. Analysis of the trajectories reveals on-pathway encounter complex formation, which is driven by electrostatic interactions between negatively charged carboxylate groups in the peptide and positively charged side chains surrounding the binding site. In contrast, the final stereospecific complex, which matches the crystal structure, features completely different interactions, namely the burial of the hydrophobic side chain of the peptide C-terminal residue and backbone hydrogen bonds. The simulations show that nonnative salt bridges stabilize kinetically the encounter complex during binding. Unbinding follows the inverse sequence of events with the same nonnative salt bridges in the encounter complex. Thus, in contrast to protein folding, which is driven by native interactions, the binding of charged peptides can be steered by nonnative interactions, which might be a general mechanism, e.g., in the recognition of histone tails by bromodomains.


Help-Seeking for Severe Intimate Partner Violence Among Sexual and Gender Minority Adolescents and Young Adults Assigned Female at birth: A Latent Class Analysis.
Sexual and gender minority adolescents and young adults assigned female at birth (SGM-AFAB) report high rates of intimate partner violence (IPV) victimization. Despite adverse health outcomes of IPV, many survivors, particularly SGM-AFAB, do not seek help. This study (1) examined the proportion of SGM-AFAB who reported severe IPV victimization who sought help; (2) elucidated patterns of help-seeking facilitators and barriers; and (3) identified associations between sociodemographic characteristics, IPV victimization types, and minority stressors and latent classes of help-seeking facilitators and barriers. Participants included 193 SGM-AFAB (Mage = 20.6, SD = 3.4; 65.8% non-monosexual; 73.1% cisgender; 72.5% racial/ethnic minority; 16.6% annual household income $20,000 or less). Most participants who experienced severe IPV did not seek help (62.2%). Having a person or provider who was aware of the participant's abusive relationship was the most common reason for seeking help (50; 68.5%). Minimizing IPV was the most common reason for not seeking help (103; 87.3%). Fewer than 5% of SGM-AFAB who experienced severe IPV and who did not seek help reported SGM-specific help-seeking barriers, including not wanting to contribute to negative perceptions of the LGBTQ community, not disclosing their SGM status, and perceiving a lack of tailored services. Help-seeking facilitators and barriers varied by sociodemographic characteristics. Three classes of help-seeking facilitators and two classes of help-seeking barriers emerged. SGM-AFAB subgroups based on sexual and gender identity, recent coercive control, and identity as IPV victims differed in latent classes. This study's findings confirm SGM-AFAB IPV survivors' low likelihood of seeking help. Our results also underscore the importance of continuing to bolster SGM-AFAB survivors' access to trauma-informed, culturally sensitive, and affirming support. Further, multilevel prevention and intervention efforts are needed to reduce minimization of abuse and anticipatory judgment and blame among SGM-AFAB who hold multiple marginalized identities, experience coercive control, and identify as IPV victims.


Bat rabies surveillance in Europe.
Rabies is the oldest known zoonotic disease and was also the first recognized bat associated infection in humans. To date, four different lyssavirus species are the causative agents of rabies in European bats: the European Bat Lyssaviruses type 1 and 2 (EBLV-1, EBLV-2), the recently discovered putative new lyssavirus species Bokeloh Bat Lyssavirus (BBLV) and the West Caucasian Bat Virus (WCBV). Unlike in the new world, bat rabies cases in Europe are comparatively less frequent, possibly as a result of varying intensity of surveillance. Thus, the objective was to provide an assessment of the bat rabies surveillance data in Europe, taking both reported data to the WHO Rabies Bulletin Europe and published results into account. In Europe, 959 bat rabies cases were reported to the RBE in the time period 1977-2010 with the vast majority characterized as EBLV-1, frequently isolated in the Netherlands, North Germany, Denmark, Poland and also in parts of France and Spain. Most EBLV-2 isolates originated from the United Kingdom (UK) and the Netherlands, and EBLV-2 was also detected in Germany, Finland and Switzerland. Thus far, only one isolate of BBLV was found in Germany. Published passive bat rabies surveillance comprised testing of 28 of the 52 different European bat species for rabies. EBLV-1 was isolated exclusively from Serotine bats (Eptesicus serotinus and Eptesicus isabellinus), while EBLV-2 was detected in 14 Daubenton's bats (Myotis daubentonii) and 5 Pond bats (Myotis dasycneme). A virus from a single Natterer's bat (Myotis nattereri) was characterized as BBLV. During active surveillance, only oral swabs from 2 Daubenton's bats (EBLV-2) and from several Eptesicus bats (EBLV-1) yielded virus positive RNA. Virus neutralizing antibodies against lyssaviruses were detected in various European bat species from different countries, and its value and implications are discussed.


Microwave synthesis of mixed ligand diimine-thiosemicarbazone complexes of ruthenium(II): biophysical reactivity and cytotoxicity.
A novel microwave-assisted synthetic method has been used to synthesise a series of mixed ligand ruthenium(II) compounds containing diimine as well as bidentate thiosemicarbazone ligands. The compounds contain the diimine 1,10-phenanthroline (phen) or 2,2'-bipyridine (bpy) and the thiosemicarbazone is derived from 9-anthraldehyde. Based on elemental analyses and spectroscopic data, the compounds are best formulated as [(phen)(2)Ru(thiosemicarbazone)](PF(6))(2) and [(phen)(2)Ru(thiosemicarbazone)](PF(6))(2) where thiosemicarbazone = 9-anthraldehydethiosemicarbazone, 9-anthraldehyde-N(4)-methylthiosemicarbazone, and 9-anthraldehyde-N(4)-ethylthiosemicarbazone. Fluorescence competition studies with ethidium bromide, along with viscometric measurements suggests that the complexes bind calf thymus DNA (CTDNA) relatively strongly via an intercalative mode possibly involving the aromatic rings of the diimine ligands. The complexes show good cytotoxic profiles against MCF-7 and MDA-MB-231 (breast adenocarcinoma) as well as HCT 116 and HT-29 (colorectal carcinoma) cell lines.


A non-linear association between self-reported negative emotional response to stress and subsequent allostatic load: prospective results from the Whitehall II cohort study.
Previous research suggests that high levels of negative emotions may affect health. However, it is likely that the absence of an emotional response following stressful events may also be problematic. Accordingly, we investigated whether a non-linear association exists between negative emotional response to major life events and allostatic load, a multisystem indicator of physiological dysregulation. Study sample was 6764 British civil service workers from the Whitehall II cohort. Negative emotional response was assessed by self-report at baseline. Allostatic load was calculated using cardiovascular, metabolic and immune function biomarkers at three clinical follow-up examinations. A non-linear association between negative emotional response and allostatic load was observed: being at either extreme end of the distribution of negative emotional response increased the risk of physiological dysregulation. Allostatic load also increased with age, but the association between negative emotional response and allostatic load remained stable over time. These results provide evidence for a more nuanced understanding of the role of negative emotions in long-term physical health.


Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression.
SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) produced by dysregulation of c-myc in the kidneys. Our previous demonstration that c-myc is overexpressed in human autosomal polycystic kidney disease (ADPKD) prompted us to investigate the pathogenetic role of c-myc in the induction and progression of the cystogenic phenotype in our mouse model. In young SBM kidneys, c-myc was two- to threefold increased with persistent expression levels into adulthood, an age when c-myc is normally undetectable. In situ hybridization analysis of the c-myc transgene demonstrated intense signal specifically overlying glomerular and tubular epithelium of developing cysts in fetal and young kidneys. Increased expression of c-myc correlated with the initiation and progression of the PKD phenotype as evidenced by early tubular and glomerular cysts at E16.5. Cyst number and size increased with age, with co-development of glomerular and tubular epithelial hyperplasia. Consistently, the mean renal proliferative index was increased approximately 5- to 20-fold in noncystic and cystic tubules of newborn SBM animals compared with littermate controls. Similarly, in fetal and newborn kidneys the tubular apoptotic indices were increased approximately three- to ninefold over controls. Both proliferation and apoptotic rates in cystic tubules approached levels in developing tubules from the normal nephrogenic zone. We conclude that the pathogenesis of PKD hinges on a critical imbalance in c-myc regulation of the opposing processes of cell proliferation and apoptosis, recapitulating the cellular phenomena in developing fetal kidney.


Identification and mapping of open chromatin regions within a 140 kb polygenic locus of human chromosome 19 using E. coli Dam methylase.
Using transient expression of the E. coli Dam methylase gene and analysis of the distribution of methylated GATC sites, we studied the distribution of open chromatin regions within a 140 kb long human genome segment in HEK-293 cells. Dam methylated sites were found in gene introns, exons, and intergenic regions, and their distribution along DNA was uneven. There were regions of high and low density of Dam methylated GATC sites, presumably corresponding to "open" and "closed" chromatin regions, respectively, and to the functional profile of the genomic locus under study. The Dam methylation profile was also generally in agreement with transcriptional activity of genes in the locus. Moreover, DNA regions accessible to Dam methylase apparently coincided with those hypersensitive to DNase I.


Total coliforms, arsenic and cadmium exposure through drinking water in the Western Region of Ghana: application of multivariate statistical technique to groundwater quality.
In recent times, surface water resource in the Western Region of Ghana has been found to be inadequate in supply and polluted by various anthropogenic activities. As a result of these problems, the demand for groundwater by the human populations in the peri-urban communities for domestic, municipal and irrigation purposes has increased without prior knowledge of its water quality. Water samples were collected from 14 public hand-dug wells during the rainy season in 2013 and investigated for total coliforms, Escherichia coli, mercury (Hg), arsenic (As), cadmium (Cd) and physicochemical parameters. Multivariate statistical analysis of the dataset and a linear stoichiometric plot of major ions were applied to group the water samples and to identify the main factors and sources of contamination. Hierarchal cluster analysis revealed four clusters from the hydrochemical variables (R-mode) and three clusters in the case of water samples (Q-mode) after z score standardization. Principal component analysis after a varimax rotation of the dataset indicated that the four factors extracted explained 93.3 % of the total variance, which highlighted salinity, toxic elements and hardness pollution as the dominant factors affecting groundwater quality. Cation exchange, mineral dissolution and silicate weathering influenced groundwater quality. The ranking order of major ions was Na(+) > Ca(2+) > K(+) > Mg(2+) and Cl(-) > SO4 (2-) > HCO3 (-). Based on piper plot and the hydrogeology of the study area, sodium chloride (86 %), sodium hydrogen carbonate and sodium carbonate (14 %) water types were identified. Although E. coli were absent in the water samples, 36 % of the wells contained total coliforms (Enterobacter species) which exceeded the WHO guidelines limit of zero colony-forming unit (CFU)/100 mL of drinking water. With the exception of Hg, the concentration of As and Cd in 79 and 43 % of the water samples exceeded the WHO guideline limits of 10 and 3 μg/L for drinking water, respectively. Reported values in some areas in Nigeria, Malaysia and USA indicated that the maximum concentration of Cd was low and As was high in this study. Health risk assessment of Cd, As and Hg based on average daily dose, hazard quotient and cancer risk was determined. In conclusion, multiple natural processes and anthropogenic activities from non-point sources contributed significantly to groundwater salinization, hardness, toxic element and microbiological contamination of the study area. The outcome of this study can be used as a baseline data to prioritize areas for future sustainable development of public wells.


Flt-3 ligand reverses late allergic response and airway hyper-responsiveness in a mouse model of allergic inflammation.
Flt3 ligand (Flt3-L) is a growth factor for dendritic cells and induces type 1 T cell responses. We recently reported that Flt3-L prevented OVA-induced allergic airway inflammation and suppressed late allergic response and airway hyper-responsiveness (AHR). In the present study we examined whether Flt3-L reversed allergic airway inflammation in an established model of asthma. BALB/c mice were sensitized and challenged with OVA, and AHR to methacholine was established. Then mice with AHR were randomized and treated with PBS or 6 microg of Flt3-L i.p. for 10 days. Pulmonary functions and AHR to methacholine were examined after rechallenge with OVA. Treatment with Flt3-L of presensitized mice significantly suppressed (p < 0.001) the late allergic response, AHR, bronchoalveolar lavage fluid total cellularity, absolute eosinophil counts, and inflammation in the lung tissue. There was a significant decrease in proinflammatory cytokines (TNF-alpha, IL-4, and IL-5) in bronchoalveolar lavage fluid, with a significant increase in serum IL-12 and a decrease in serum IL-5 levels. There was no significant effect of Flt3-L treatment on serum IL-4 and serum total IgE levels. Sensitization with OVA significantly increased CD11b(+)CD11c(+) cells in the lung, and this phenomenon was not significantly affected by Flt3-L treatment. These data suggest that Flt3-L can reverse allergic airway inflammation and associated changes in pulmonary functions in murine asthma model.


The Representational Basis of Working Memory.
Working memory refers to a system involved in the online maintenance and manipulation of information in the absence of external input. Due to the importance of working memory in higher-level cognition, a wealth of neuroscience studies has investigated its neural basis. These studies have often led to conflicting viewpoints regarding the importance of the prefrontal cortex (PFC) and posterior sensory cortices. Here, we review evidence for each position. We suggest that the relative contributions of the PFC and sensory cortices to working memory can be understood with respect to processing demands. We argue that procedures that minimize processing demands lead to increased importance of sensory representations, while procedures that permit transformational processing lead to representational abstraction that relies on the PFC. We suggest that abstract PFC representations support top-down control over posterior representations while also providing bottom-up inputs into higher-level cognitive processing. Although a number of contemporary studies have studied working memory while using procedures that minimize the role of the PFC, we argue that consideration of the PFC is critical for our understanding of working memory and higher-level cognition more generally.


Circadian clocks and adaptation in Arabidopsis.
Endogenous circadian rhythms are almost ubiquitous among organisms from cyanobacteria to mammals and regulate diverse physiological processes. It has been suggested that having an endogenous circadian system enables an organism to anticipate periodic environmental changes and adapt its physiological and developmental states accordingly, thus conferring a fitness advantage. However, it is hard to measure fitness directly and there is, to date, only limited evidence supporting the assumption that having a circadian system can increase fitness and therefore be adaptive. In this article, we report an evolutionary approach to examine the adaptive significance of a circadian system. By crossing Arabidopsis thaliana plants containing mutations that cause changes in circadian rhythms, we have created heterozygous 'Mother' (F1) plants with genetic variance for circadian rhythmicity. The segregating F2 offspring present a range of circadian rhythm periods. We have applied a selection to the F2 plants of short and long T-cycles under different competition strengths and found that the average phenotype of circadian period of the resulting F3 plants show a strong positive correlation with the T-cycle growth conditions for the competing F2 plants. Consistent with their circadian phenotypes, the frequency of long-period alleles was altered in the F3 plants. Our results show that F2 plants with endogenous rhythms that more closely match the environmental T-cycle are fitter, producing relatively more viable offspring in the F3 population. Thus, having a circadian clock that matches with the environment is adaptive in Arabidopsis.


Influence of infiltrant application time on the reduction of opaqueness of proximal enamel caries.
Infiltrant resins were developed to hamper carious lesion progression and mask the whitish appearance of first evidence of caries. This study aimed at testing the hypothesis that a long application time of resin infiltrant in proximal enamel caries improves esthetic outcome compared to the commercially recommended time. Twenty teeth with uncavitated inactive proximal white enamel caries lesions (selected by two calibrated examiners; inter-examiner κ = 0.87) were divided into two groups (experimental and control group; n = 10) that agreed regarding lesion surface area. Lesions were infiltrated following the protocol recommended by the manufacturer (two applications, 3 min application first and another 1 min application later; control) and by the protocol tested in this study (one application of 30 min; experimental). Enamel opaqueness (esthetic outcome) was measured by a calibrated examiner (intra-class coefficient of 0.9) before and after infiltration using fluorescence microscopy. Reduction of enamel opaqueness was significantly higher in the experimental group (40.0% ± 18.5%) than in the control group (18.6% ± 14.9%) (P = 0.0105, one-tailed t-test; Hedge's g of 1.28, 95% confidence interval of 0.43/2.13, and power of 86%). It can be concluded that the application time of 30 min provides a greater reduction in opaqueness of proximal enamel lesion compared to the application time recommended by the manufacturer. The high effect size could stimulate patients to comply with the treatment time.


Coronavirus (COVID-19) infection - impact on cardiovascular system.
This review aimed to explain novel coronavirus (COVID-19) infection impact on cardiovascular system and patients management in community and primary care settings. Literature search and review limited to 2020 of published papers identified dealing with Coronavirus and cardiovascular disease. Coronavirus is a large family of positive-sense, enveloped, single-stranded RNA viruses that belong to the Nidovirales order. Covid-19 refers to infection with the SARS-CoV-2 variant. Myocardial injury has a considerable association with mortality outcomes for COVID-19 infection. The prognosis of patients with underlying cardiovascular diseases, who had not sustained myocardial injury was relatively favourable. Inflammation may also be a potential mechanism for myocardial injury. So far, current evidence suggests statistically significant associations between cardiac injury and mortality in patients with COVID-19. Whether this is mediated by destruction of angiotensin converting enzyme 2 in heart cells or by other mechanisms, is being investigated. In patients with underlying cardiovascular diseases, aggressive treatment for COVID-19 should be considered and clinicians should be aware of the significantly increased risk of serious infection and worse prognosis in this patient group. New evidence and studies are continually emerging and will confirm or refute our current understanding about COVID-19 impact. Primary care practitioners are urged to continue to monitor the evolving evidence to appropriately manage their patients who are at risk of, or currently diagnosed with cardiovascular conditions.


A Revision of the Pseudotropheus elongatus species group (Teleostei: Cichlidae) With Description of a New Genus and Seven New Species.
Lake Malaŵi is known for its endemic haplochromine species flock, most notably the rock-dwelling cichlids known as mbuna. The group of mbuna referred to as the Pseudotropheus elongatus species group is currently comprised of Metriaclima spp., Tropheops spp., Cynotilapia spp., and Pseudotropheus spp. In this study, Chindongo, a new genus with the type species C. bellicosus, is described for additional species in this group. Chindongo is distinguished from other mbuna genera by 1) the presence of bicuspid teeth in the anterior portion of the outer row of both upper and lower jaw; 2) a moderately to steeply sloped vomer with a narrow rostral tip which makes an angle of between 53° and 68° with the parasphenoid; 3) a small mouth with the lower jaw slightly shorter than the upper; 4) a broad anterior dentigerous area on both premaxilla and dentary with three or more rows of teeth (usually 5-6 rows); 5) a flank melanin pattern consisting of vertical bars without horizontal elements at any stage of development. Chindongo bellicosus is distinguished by its color pattern and shallower body from the other species which we have transferred to Chindongo. We also describe six new elongate mbuna species and place them into three available genera, they include: Metriaclima flavicauda, M. usisyae, Tropheops kumwera, T. biriwera, T. kamtambo, and Cynotilapia chilundu.


Distinct physiological functions of thiol peroxidase isoenzymes in Saccharomyces cerevisiae.
A new type of peroxidase ("thiol peroxidase"; TPx) having cysteine as the primary site of catalysis has been discovered from prokaryotes to eukaryotes. In addition to two yeast TPx isoforms (TSA I and TSA II/AHPC1) previously described, three additional TPx homologues were identified by analysis of the open reading frame data base for Saccharomyces cerevisiae. Three novel isoforms showed a distinct thiol peroxidase activity supported by thioredoxin, and appeared to be distinctively localized in cytoplasm, mitochondria, and nucleus. Each isoform was named after its subcellular localization such as cytoplasmic TPx I (cTPx I or TSA I), cTPx II, cTPx III (TSA II/AHPC1), mitochondrial TPx (mTPx), and nuclear TPx (nTPx). Their transcriptional activities suggest that cTPx I and cTPx III are the most predominant isoforms among the five type isoforms. Transcriptional activities of TPx isoenzymes during yeast life span were quite different from each other. Unlike other TPx null mutants, cTPx I null mutant was hypersensitive to various oxidants except for 4-nitroquinoline N-oxide. The null mutant was more resistant toward 4-nitroquinoline N-oxide and acidic culture than its wild type. The severe growth retardation of cTPx II mutant resulted in accumulation of G(1)-phased cells. Based on kinetic properties of five isoforms, their subcellular localizations, and distinct physiology of each null mutant, we discussed the physiological functions of five types of TPx isoenzymes in yeast throughout the full growth cycle.


Collective feature selection to identify crucial epistatic variants.
Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called "short fat data" problem. The efficiency of machine learning methods can be increased by limiting the number of input features. Thus, it is very important to perform variable selection before searching for epistasis. Many methods have been evaluated and proposed to perform feature selection, but no single method works best in all scenarios. We demonstrate this by conducting two separate simulation analyses to evaluate the proposed collective feature selection approach. Through our simulation study we propose a collective feature selection approach to select features that are in the "union" of the best performing methods. We explored various parametric, non-parametric, and data mining approaches to perform feature selection. We choose our top performing methods to select the union of the resulting variables based on a user-defined percentage of variants selected from each method to take to downstream analysis. Our simulation analysis shows that non-parametric data mining approaches, such as MDR, may work best under one simulation criteria for the high effect size (penetrance) datasets, while non-parametric methods designed for feature selection, such as Ranger and Gradient boosting, work best under other simulation criteria. Thus, using a collective approach proves to be more beneficial for selecting variables with epistatic effects also in low effect size datasets and different genetic architectures. Following this, we applied our proposed collective feature selection approach to select the top 1% of variables to identify potential interacting variables associated with Body Mass Index (BMI) in ~ 44,000 samples obtained from Geisinger's MyCode Community Health Initiative (on behalf of DiscovEHR collaboration). In this study, we were able to show that selecting variables using a collective feature selection approach could help in selecting true positive epistatic variables more frequently than applying any single method for feature selection via simulation studies. We were able to demonstrate the effectiveness of collective feature selection along with a comparison of many methods in our simulation analysis. We also applied our method to identify non-linear networks associated with obesity.


Edwards Thermodynamics for a Driven Athermal System with Dry Friction.
We obtain, using semianalytical transfer operator techniques, the Edwards thermodynamics of a one-dimensional model of blocks connected by harmonic springs and subjected to dry friction. The theory is able to reproduce the linear divergence of the correlation length as a function of energy density observed in direct numerical simulations of the model under tapping dynamics. We further characterize analytically this divergence using a Gaussian approximation for the distribution of mechanically stable configurations, and show that it is related to the existence of a peculiar infinite temperature critical point.


The design of novel 17beta-hydroxysteroid dehydrogenase type 3 inhibitors.
17beta-Hydroxysteroid dehydrogenase type 3 (17beta-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17beta-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for small molecule inhibitors for the treatment of prostate cancer. Here we report the design of selective inhibitors of 17beta-HSD3 as potential anti-cancer agents. Due to 17beta-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17beta-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17beta-HSD3 with an IC(50)=700nM resulting in the discovery of a novel lead series for further optimisation. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17beta-HSD3 with an IC(50) approximately 200nM.


The European accreditation of Istituto Tumori Giovanni Paolo II of Bari.
The National Cancer Institute of Bari (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS) has been involved since the conception of the project of the Italian Ministry for Health aimed to validate the applicability of the Organisation of European Cancer Institutes (OECI) accreditation and designation (A&D) model to the Network of Italian Cancer Centers, IRCCS, of Alleanza Contro il Cancro. The self-assessment phase of the Institute started in September 2013 and ended in June 2014. All documents and tools were transferred to the OECI A&D Board in June 2014 and a 2-day peer review visit was conducted in October 2014 by an international qualified audit team. The Institute received its final designation and certification in June 2015. The OECI A&D Board, in its final report, came to the conclusion that Istituto Tumori "Giovanni Paolo II" of Bari has a strong research component with some essential elements of comprehensive cancer care still under development; the lack of a system for using outcome data for the strategic management approach to decision-making and missing a regular internal audit system eventually helping further quality improvement were reported as examples of areas with opportunities for improvement. The OECI A&D process represented a great opportunity for the cancer center to benchmark the quality of its performance according to standard parameters in comparison with other international centers and to further develop a participatory group identity. The common goal of accreditation was real and participatory with long-lasting positive effects. We agree with the OECI comments about the next areas of work in which the Institute could produce future further efforts: the use of its powerful IT system as a means for outcome analysis and empowerment projects for its cancer patients.


Anti-high-mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis.
High-mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxin shock, intraabdominal sepsis, and acute lung injury, and a promising therapeutic target of severe sepsis. We sought to investigate the effect of antibodies to HMGB1 on severe sepsis in a rat cecal ligation and puncture (CLP) model. Adult male Sprague-Dawley rats underwent CLP and then were randomly divided into two groups: treatment with anti-HMGB1 polyclonal antibodies, and non-immune IgG-treated controls. The serum HMGB1 concentrations were measured at ten time points (preoperatively, and postoperatively at 4, 8, 20, 32, and 48 h and at 3, 4, 5, and 6 days). Hematoxylin-eosin staining, elastica-Masson staining, and immunohistochemical staining for HMGB1 were performed on the cecum and the lung to assess pathological changes 24 h after the CLP procedure. Treatment with anti-HMGB1 antibodies significantly increased survival [55% (anti-HMGB1) vs. 9% (controls); P< 0.01]. The serum HMGB1 concentrations at postoperative hours 20 and 32 of the anti-HMGB1 antibody-treated animals were significantly lower than those of the controls (P < 0.05). Treatment with anti-HMGB1 antibodies markedly diminished the pathological changes and the number of HMGB1-positive cells in the cecum and the lung. The present study demonstrates that anti-HMGB1 antibodies are effective in the treatment of severe sepsis in a rat model, thereby supporting the relevance of HMGB1 eradication therapy for severe sepsis.


Antibiotic resistance of bacterial biofilms.
A biofilm is a structured consortium of bacteria embedded in a self-produced polymer matrix consisting of polysaccharide, protein and DNA. Bacterial biofilms cause chronic infections because they show increased tolerance to antibiotics and disinfectant chemicals as well as resisting phagocytosis and other components of the body's defence system. The persistence of, for example, staphylococcal infections related to foreign bodies is due to biofilm formation. Likewise, chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is caused by biofilm-growing mucoid strains. Characteristically, gradients of nutrients and oxygen exist from the top to the bottom of biofilms and these gradients are associated with decreased bacterial metabolic activity and increased doubling times of the bacterial cells; it is these more or less dormant cells that are responsible for some of the tolerance to antibiotics. Biofilm growth is associated with an increased level of mutations as well as with quorum-sensing-regulated mechanisms. Conventional resistance mechanisms such as chromosomal beta-lactamase, upregulated efflux pumps and mutations in antibiotic target molecules in bacteria also contribute to the survival of biofilms. Biofilms can be prevented by early aggressive antibiotic prophylaxis or therapy and they can be treated by chronic suppressive therapy. A promising strategy may be the use of enzymes that can dissolve the biofilm matrix (e.g. DNase and alginate lyase) as well as quorum-sensing inhibitors that increase biofilm susceptibility to antibiotics.


Saccharomyces cerevisiae fermentation product in dairy cow diets containing dried distillers grains plus solubles.
Sixteen multiparous Holstein cows (127+/-52 d in milk) were used in 4 replicated 4 x 4 Latin squares with 4-wk periods to evaluate interactions of dietary inclusion of a fermentation product of Saccharomyces cerevisiae (SC; XPC, Diamond V Mills, Cedar Rapids, IA) and dried distillers grains plus solubles (DDGS) on production of milk and milk components when fed diets containing approximately 30% dietary neutral detergent fiber with calculated forage neutral detergent fiber of 19.3% of diet dry matter (DM). Treatments were a 2 x 2 factorial arrangement with SC included at 0 or 14 g/d and DDGS at 0 or 20% of diet DM. Diets consisted of 27% corn silage, 18% alfalfa hay, and 55% concentrate mix on a DM basis. Diets not containing DDGS included additional corn, soybean meal, expeller soybean meal, soyhulls, and rumen inert fat to remain isocaloric and isonitrogenous with DDGS diets. Dry matter intake (26.0 kg/d) was similar for all diets. Milk production increased with the addition of SC to diets (43.6 vs. 42.0 kg/d for diets without SC) and decreased for cows fed diets containing DDGS (42.0 kg/d vs. 43.6 kg/d for diets not containing DDGS). Milk fat percentage (3.05 vs. 3.22% for DDGS and non-DDGS diets, respectively) and yield (1.27 vs. 1.41 kg/d) were decreased by the addition of DDGS but were not affected by the addition of SC. Concentrations of long-chain, polyunsaturated, trans-, and conjugated fatty acids in milk of cows fed DDGS were increased, but milk fatty acid profiles were not affected by SC. Milk true protein concentrations were similar for all diets; however, the addition of SC increased yield of true protein (1.32 vs. 1.27 kg/d). Concentrations of milk urea nitrogen increased when SC was included in the diet with DDGS. The DDGS decreased yields of energy-corrected milk (39.4 vs. 42.1 kg/d) and tended to decrease feed efficiency (1.53 vs. 1.61 kg of energy-corrected milk/kg of dry matter intake). Body weights and condition scores were not affected by treatments. Results suggest that diets containing minimal amounts of forage fiber and DDGS at 20% of diet DM will contribute to decreased milk production and milk fat depression. The addition of SC did improve milk and milk protein yields but did not prevent milk fat depression caused by DDGS. Production responses to SC were similar when cows were fed DDGS or non-DDGS diets.


FPGA-based LDPC-coded APSK for optical communication systems.
In this paper, with the aid of mutual information and generalized mutual information (GMI) capacity analyses, it is shown that the geometrically shaped APSK that mimics an optimal Gaussian distribution with equiprobable signaling together with the corresponding gray-mapping rules can approach the Shannon limit closer than conventional quadrature amplitude modulation (QAM) at certain range of FEC overhead for both 16-APSK and 64-APSK. The field programmable gate array (FPGA) based LDPC-coded APSK emulation is conducted on block interleaver-based and bit interleaver-based systems; the results verify a significant improvement in hardware efficient bit interleaver-based systems. In bit interleaver-based emulation, the LDPC-coded 64-APSK outperforms 64-QAM, in terms of symbol signal-to-noise ratio (SNR), by 0.1 dB, 0.2 dB, and 0.3 dB at spectral efficiencies of 4.8, 4.5, and 4.2 b/s/Hz, respectively. It is found by emulation that LDPC-coded 64-APSK for spectral efficiencies of 4.8, 4.5, and 4.2 b/s/Hz is 1.6 dB, 1.7 dB, and 2.2 dB away from the GMI capacity.


Structural disjoining potential for grain-boundary premelting and grain coalescence from molecular-dynamics simulations.
We describe a molecular-dynamics framework for the direct calculation of the short-ranged structural forces underlying grain-boundary premelting and grain coalescence in solidification. The method is applied in a comparative study of (i) a Sigma9115120 degrees twist and (ii) a Sigma9110{411} symmetric tilt boundary in a classical embedded-atom model of elemental Ni. Although both boundaries feature highly disordered structures near the melting point, the nature of the temperature dependence of the width of the disordered regions in these boundaries is qualitatively different. The former boundary displays behavior consistent with a logarithmically diverging premelted layer thickness as the melting temperature is approached from below, while the latter displays behavior featuring a finite grain-boundary width at the melting point. It is demonstrated that both types of behavior can be quantitatively described within a sharp-interface thermodynamic formalism involving a width-dependent interfacial free energy, referred to as the disjoining potential. The disjoining potential for boundary (i) is calculated to display a monotonic exponential dependence on width, while that of boundary (ii) features a weak attractive minimum. The results of this work are discussed in relation to recent simulation and theoretical studies of the thermodynamic forces underlying grain-boundary premelting.


Identification of high caspase-3 mRNA expression as a unique signature profile for extremely old individuals.
Apoptosis, or programmed cell death, is important for maintaining tissue homeostasis, as it permits the elimination of damaged, functionless or unwanted cells. As we age, our immune system undergoes constant remodeling, during which age-associated changes in immune parameters, including decreased naïve and increased memory T cells, have been reported. However, excessive immune cell loss, rendering the elderly more vulnerable to infections, and inappropriate deletion of damaged or functionless lymphocytes, can contribute to the development of age-associated diseases. As such, we studied the mRNA expression of cell death (specifically caspase) genes in nonagenarians and centenarians, successful models of ageing who have survived or avoided age-associated diseases, as well as in their younger counterparts and found that population composed of extremely old individuals shows a unique pattern of caspase mRNA expression, characterized by high levels of caspase-1 and -3, and low levels of caspase-8, mRNA while those composed of old individuals are characterize by high level of caspase-8 mRNA expression. Furthermore, we show that the described changes in caspases mRNA do not appear to results from age-related changes in PBMC composition, such as decreases in CD24. Therefore, we suggest that unique patterns of caspase mRNA results from the regulation of message abundance on a per cell basis, via a putative regulation of caspase genes at the transcription or RNA processing level, rather than changes in immune profiles.


Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis.
In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA(+) T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.


Mitochondrial DNA variability in Bosnians and Slovenians.
Mitochondrial DNA variability in two Slavonic-speaking populations of the northwestern Balkan peninsula, Bosnians (N = 144) and Slovenians (N = 104), was studied by hypervariable segments I and II (HVS I and II) sequencing and restriction fragment-length polymorphism (RFLP) analysis of the mtDNA coding region. The majority of the mtDNA detected in Southern Slavonic populations falls into the common West Eurasian mitochondrial haplogroups (e.g., H, pre-V, J, T, U, K, I, W, and X). About 2% of the Bosnian mtDNAs encompass East Eurasian and African lineages (e.g., M and L1b, respectively). The distribution of mtDNA subclusters in Bosnians, Slovenians and the neighbouring European populations reveals that the common genetic substratum characteristic for Central and Eastern European populations (such as Germans, Poles, Russians and Finns) penetrates also South European territories as far as the Western Balkans. However, the observed differentiation between Bosnian and Slovenian mtDNAs suggests that at least two different migration waves of the Slavs may have reached the Balkans in the early Middle Ages.


Asymptomatic cardiac disease following mediastinal irradiation.
This study was designed to evaluate the potential benefit of screening previously irradiated patients with echocardiography. Mediastinal irradiation is known to cause cardiac disease. However, the prevalence of asymptomatic cardiac disease and the potential for intervention before symptom development are unknown. We recruited 294 asymptomatic patients (mean age 42 +/- 9 years, 49% men, mean mantle irradiation dose 43 +/- 0.3 Gy) treated with at least 35 Gy to the mediastinum for Hodgkin's disease. After providing written consent, each patient underwent electrocardiography and transthoracic echocardiography. Valvular disease was common and increased with time following irradiation. Patients who had received irradiation more than 20 years before evaluation had significantly more mild or greater aortic regurgitation (60% vs. 4%, p < 0.0001), moderate or greater tricuspid regurgitation (4% vs. 0%, p = 0.06), and aortic stenosis (16% vs. 0%, p = 0.0008) than those who had received irradiation within 10 years. The number needed to screen to detect one candidate for endocarditis prophylaxis was 13 (95% confidence interval [CI] 7 to 44) for patients treated within 10 years and 1.6 (95% CI 1.3 to 1.9) for those treated at least 20 years ago. Compared with the Framingham Heart Study population, mildly reduced left ventricular fractional shortening (<30%) was more common (36% vs. 3%), and age- and gender-adjusted left ventricular mass was lower (90 +/- 27 g/m vs. 117 g/m) in irradiated patients. There is a high prevalence of asymptomatic heart disease in general, and aortic valvular disease in particular, following mediastinal irradiation. Screening echocardiography should be considered for patients with a history of mediastinal irradiation.


In vitro cleaning potential of three different implant debridement methods.
To assess the cleaning potential of three different instrumentation methods commonly used for implant surface decontamination in vitro, using a bone defect-simulating model. Dental implants were stained with indelible ink and mounted in resin models, which represented standardized peri-implantitis defects with different bone defect angulations (30, 60 and 90°). Cleaning procedures were performed by either an experienced dental hygienist or a 2nd-year postgraduate student. The treatment was repeated 20 times for each instrumentation, that is, with a Gracey curette, an ultrasonic device and an air powder abrasive device (PAD) with glycine powder. After each run, implants were removed and images were taken to detect color remnants in order to measure planimetrically the cumulative uncleaned surface area. SEM images were taken to assess micromorphologic surface changes (magnification 10,000 ×). Results were tested for statistical differences using two-way ANOVA and Bonferroni correction. The areas of uncleaned surfaces (%, mean ± standard deviations) for curettes, ultrasonic tips, and airflow accounted for 24.1 ± 4.8%, 18.5 ± 3.8%, and 11.3 ± 5.4%, respectively. These results were statistically significantly different (P < 0.0001). The cleaning potential of the airflow device increased with wider defects. SEM evaluation displayed distinct surface alterations after instrumentation with steel tips, whereas glycine powder instrumentation had only a minute effect on the surface topography. Within the limitations of the present in vitro model, airflow devices using glycine powders seem to constitute an efficient therapeutic option for the debridement of implants in peri-implantitis defects. Still, some uncleaned areas remained. In wide defects, differences between instruments are more accentuated.


Further study of the intrinsic safety of internally shorted lithium and lithium-ion cells within methane-air.
National Institute for Occupational Safety and Health (NIOSH) researchers continue to study the potential for lithium and lithium-ion battery thermal runaway from an internal short circuit in equipment for use in underground coal mines. Researchers conducted cell crush tests using a plastic wedge within a 20-L explosion-containment chamber filled with 6.5% CH4-air to simulate the mining hazard. The present work extends earlier findings to include a study of LiFePO4 cells crushed while under charge, prismatic form factor LiCoO2 cells, primary spiral-wound constructed LiMnO2 cells, and crush speed influence on thermal runaway susceptibility. The plastic wedge crush was a more severe test than the flat plate crush with a prismatic format cell. Test results indicate that prismatic Saft MP 174565 LiCoO2 and primary spiral-wound Saft FRIWO M52EX LiMnO2 cells pose a CH4-air ignition hazard from internal short circuit. Under specified test conditions, A123 systems ANR26650M1A LiFePO4 cylindrical cells produced no chamber ignitions while under a charge of up to 5 A. Common spiral-wound cell separators are too thin to meet intrinsic safety standards provisions for distance through solid insulation, suggesting that a hard internal short circuit within these cells should be considered for intrinsic safety evaluation purposes, even as a non-countable fault. Observed flames from a LiMnO2 spiral-wound cell after a chamber ignition within an inert atmosphere indicate a sustained exothermic reaction within the cell. The influence of crush speed on ignitions under specified test conditions was not statistically significant.


The assessment of cytotoxic T cell and natural killer cells activity in residents of high and ordinary background radiation areas of Ramsar-Iran.
The effective radiation dose of human from natural sources is about 2.4 mSv/y and the dose limit for radiation workers is 20 mSv/y. Ramsar, a city in Iran, has been the subject of concern in the last forty years for a high level of radiation measured in some spots as high as 260 mSv/y. Carcinogenesis is one of the most studied effects of radiation especially in high doses. Recent studies showed that the high level of natural radiation received by inhabitants of this area, paradoxically don't have significant health effect. Natural killer (NK) cells and cytotoxic T cells are the most important cells in tumor immune surveillance and CD107a is a widely expressed intracellular protein located in the lysosomal/endosomal membrane. CD107a transiently located on the cell membrane can be used as a marker of CD8 + T cell degranulation following stimulation. It is also expressed, to a lower extent, on activated NK cells. In this study, 60 healthy people were selected randomly and their consent obtained and confounding factors such as sex, age, life-styles was matched then the count of activated NK and CD8 + cells was compared in high and normal background radiation areas inhabitants of Ramsar. After filling the questionnaire and measurement of background radiation, blood samples of 30 healthy people from each region were analyzed immediately by means of flowcytometry. The leukocytes and their subsets were not significantly different between two groups and the count of active cells was higher in control group. The result shows that the changes in immune system occur due to radiation and maybe it is as a result of higher radiosensitivity of activated cells.


Lumbar Erector Spinae Plane Block as a Main Anesthetic Method for Hip Surgery in High Risk Elderly Patients: Initial Experience with a Magnetic Resonance Imaging.
Since initial description by Forero for thoracic region, ultrasound guided erector spinae plane (ESP) block has experienced several surgeries for postoperative pain management, chronic pain or surgical anesthesia. Although ESP block has been reported to provide effective analgesia in the thoracic region, its effect in lumbar region still unclear. In this study we aimed to showed our successful experience with lumbar ESP block as a main anesthetic technique in fifteen high risk elderly patients undergoing hip surgery with mild propofol sedation. In this observational study high risk elderly fifteen patients received lumbar ESP block as a main anesthetic technique with mild propofol sedation. 40 mL of local anesthetic mixture (20 mL bupivacaine 0.5%, 10 mL lidocaine 2%, and 10 mL normal saline) was administered between the erector spinae muscles and transverse process at the level of the 4th lumbar vertebra. Also we demonstrate magnetic resonance images and discuss the anatomic basis of lumbar ESP block. All patients' surgeries were completed without requirement for general anesthesia or local anesthesia infiltration of the surgical site. All patients' pain scores were <2/10 in the recovery room. Significant contrast spread was observed between the Th12 and L5 transverse process and erector spinae muscle and between multifidus muscle and iliocostal muscle at the L2-4 levels. Contrast material was observed at the anterior of the transverse process spreading to the paravertebral, foraminal and partially epidural area/spaces and also in the areas where the lumbar nerves enter the psoas muscle. Lumbar ESP block when combined with mild sedoanalgesia provides adequate and safe anesthesia in high risk elderly patients undergoing hip surgery.


A newborn with positive antiglobulin test whose mother took methyldopa in pregnancy.
Methyldopa is known to cause the production of autoantibodies against red blood cells (RBCs), leading to a positive direct antiglobulin test (DAT) and hemolytic anemia. In about 20% of patients taking methyldopa, IgG autoantibodies develop against RBCs. However, most of the patients do not have hemolysis. A small percentage of such DAT-positive patients, about 2% of those taking methyldopa, develop an autoimmune hemolytic anemia (AIHA). The fact that the DAT is positive in the newborn with unconjugated hyperbilirubinemia is considered as an isoimmune hemolytic disease caused by blood group incompatibility. In this article, a newborn with jaundice and positive DAT without hemolysis is reported. Her mother had the history of taking methyldopa in her pregnancy. Thus, when newborns are detected with positive DAT and jaundice, without blood group incompatibility, mothers should be questioned regarding drugs used in their pregnancy.


The prevalence of low back pain in adults: a methodological review of the literature.
The prevalence of low back pain (LBP) has been reported in the literature for different populations. Methodological differences among studies and lack of methodological rigor have made it difficult to draw conclusions from these studies. A systematic review was done for adult community prevalence studies of LBP published from 1981 to 1998. The technique of capture-recapture was performed to estimate the completeness of the search strategy used. Established guidelines and a methodological scoring system were used to critically appraise the studies. Thirteen studies were deemed methodologically acceptable. Differences in the duration of LBP used in the studies appeared to affect the prevalence rates reported and explain much of the variation seen. It was estimated that the point prevalence rate in North America is 5.6%. Further studies using superior methods are needed, however, before this estimate can be used with confidence to make health care policies and decisions relating to physical therapy.


Nonconsensus West Nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo.
West Nile virus (WNV) is similar to other RNA viruses in that it forms genetically complex populations within hosts. The virus is maintained in nature in mosquitoes and birds, with each host type exerting distinct influences on virus populations. We previously observed that prolonged replication in mosquitoes led to increases in WNV genetic diversity and diminished pathogenesis in mice without remarkable changes to the consensus genome sequence. We therefore sought to evaluate the relationships between individual and group phenotypes in WNV and to discover novel viral determinants of pathogenesis in mice and fitness in mosquitoes and birds. Individual plaque size variants were isolated from a genetically complex population, and mutations conferring a small-plaque and mouse-attenuated phenotype were localized to the RNA helicase domain of the NS3 protein by reverse genetics. The mutation, an Asp deletion, did not alter type I interferon production in the host but rendered mutant viruses more susceptible to interferon compared to wild type (WT) WNV. Finally, we used an in vivo fitness assay in Culex quinquefasciatus mosquitoes and chickens to determine whether the mutation in NS3 influenced fitness. The fitness of the NS3 mutant was dramatically lower in chickens and moderately lower in mosquitoes, indicating that RNA helicase is a major fitness determinant of WNV and that the effect on fitness is host specific. Overall, this work highlights the complex relationships that exist between individual and group phenotypes in RNA viruses and identifies RNA helicase as an attenuation and fitness determinant in WNV.


Long-term effects of pancreatic transplant function in patients with advanced juvenile-onset diabetes.
Present methods of management of juvenile-onset diabetes mellitus do not prevent serious and debilitating complications affecting multiple organ systems. In an effort to reverse advanced forms of these complications, segmental transplantation of the pancreas has been performed on 10 patients, seven of whom simultaneously or subsequently received renal transplants. Long periods of normoglycemia (two to four and one-half years) were achieved in two patients who also maintained transplant kidney function. The course of these two patients is described to illustrate the possible value and limitations of the procedure. These patients had normal blood glucose levels, exhibited repeated normal intravenous glucose tolerance curves, and had repeated normal endogenous insulin levels. Their courses were characterized by (1) absence of problems related to pancreatic exocrine secretions into the bladder; (2) stable eye changes despite some episodes of hemorrhage from preexisting retinopathy; (3) vascular complications, including stroke and gangrene of extremities necessitating amputation despite successful femoropopliteal bypass grafting; (4) peripheral neuropathy; and (5) repeated infections. Both patients succumbed to vascular complications. Thus, pancreatic transplantation can maintain blood glucose and insulin at normal levels for extended periods of time. However, it does not reverse such complications as advanced retinopathy or atherosclerosis. Since the procedure may have value in preventing progression of these complications, it should be evaluated in patients with less advanced complications of diabetes.